(Adapted from the application) The broad, long-term objective of the research proposed here is to increase knowledge about structure/function relationships for the HIV envelope glycoprotein complex (gp120/gp41). In spite of considerable efforts, it has not yet been possible to obtain a detailed structure for gp120, gp41 or the gp120/gp41 complex. Recognizing this history, new approaches to the problem, utilizing protein dissection, coupled with phage display and combinatorial chemistry, will be applied in the proposed research. The three specific aims of the proposed research are: 1. To determine the high resolution X-ray crystal structure of the trimeric core of HIV gp41. 2. To identify stable, folded subfragments of the gp120/gp41 complex by protein dissection, obtain diffraction-quality crystals of these subfragments, and solve the structures of these subfragments by X-ray crystallographic methods. 3. To identify ligands that rigidify the structure of gp120, use these ligands to obtain diffraction-quality crystals of gp120 and solve the structures of these ligand-gp120 complexes by X-ray crystallographic methods. 4. To identify D-peptide inhibitors of HIV infection, and characterize the structures of these inhibitors bound to fragments of gp41. The envelope glycoprotein (Env gp) of HIV is required for virion attachment to cells and subsequent fusion of the viral and cellular membranes. The envelope is therefore crucial for infection of cells by HIV. In addition, essentially all of the neutralizing antibody activity in HIV-1 infected hosts is directed against Env gp. For these and other reasons, determining the structure of the gp120-gp41 complex, and components thereof, has been a major goal of efforts to develop new approaches for the treatment of AIDS. In spite of numerous efforts, high- resolution structural information about Enz gp is lacking. The present proposal is aimed at obtaining this information through new approaches. This research is designed to advance our understanding of structure/function relationships of the HIV envelope, ultimately facilitating structure-based drug design for the treatment of AIDS.